BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways

Yang Zhang, Bingwei Xu, Junfeng Shi, Jieming Li, Xinlan Lu, Li Xu, Helen Yang, Nevean Hamad, Chi Wang, Dana Napier, Shuixiang He, Chunming Liu, Zeyi Liu, Hai Qian, Li Chen, Xiaowei Wei, Xucai Zheng, Jian An Huang, Olivier Thibault, Rolf CravenDongping Wei, Yueyin Pan, Binhua P. Zhou, Yadi Wu, Xiuwei H. Yang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Purpose: Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC. Methods: Two independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model. Results: We found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G+ myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation. Conclusion: Based on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.

Original languageEnglish
Pages (from-to)1049-1066
Number of pages18
JournalCellular Oncology
Volume43
Issue number6
DOIs
StatePublished - Dec 2020

Bibliographical note

Funding Information:
The study was supported in part by a grant from the American Cancer Society (#IRG 85-001-25) and a pilot project funding from a NIH COBRE grant (5P20GM121327-03) to XH Yang, and a Chinese NSF grant (81472793) to Dongping Wei. The Biospecimen Core was funded by the National Cancer Institute (P30CA177558). Ms. Lucy L Yang edited the manuscript.

Publisher Copyright:
© 2020, The Author(s).

Keywords

  • BRD4
  • FAK
  • Integrin
  • Targeted therapy
  • Triple-negative breast cancer
  • c-Myc

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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